JP2014517712A - Localized photodynamic therapy - Google Patents

Abstract

  A method for treating improved prostate cancer with photodynamic therapy targeting blood vessels and a method for planning improved therapy using the light density index to plan and guide effective treatment are presented.

Description

  Some men with early prostate cancer seek alternatives to whole-gland therapy, while others seek active surveillance without therapeutic intervention There is. There is an increasing need for selective therapies that treat cancer while preserving normal prostate tissue. Such selective therapies include a tumor-targeted approach that can distinguish between neoplastic and benign tissue and a localized therapy in which selectivity is achieved by spatially directed localized excision.

Among local treatments, photodynamic therapy (PDT), in which photosensitizers are administered systemically and tumor sites are locally photoactivated, is the development of a new generation of photosensitizers with improved properties. As a premise, it has become an increasingly attractive option. Among these novel agents, notable are metal-containing derivatives of bacteriochlorophyll, two of which are Pd-bacteriopheophorbide (padoporfin; WST09; TOOKAD®)-non-patent Reference 1; Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5—and, more recently, its improved anionic derivative, palladium 3 ¹ -oxo-15- Methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide (WST11; STAKEL (registered trademark); TOOKAD (registered trademark) Soluble (trademark)), Non-patent document 6; Non-patent document 7; Non-patent document 8 See-has advanced to human clinical trials in the last decade.

  One of the challenges faced by photodynamic therapy is a light dose that is therapeutically effective in the desired three-dimensional volume of prostate tissue without causing unacceptable incidental damage to other tissues such as the urethra and rectum. This means that it is necessary to determine a prospective treatment plan that directs the placement of the optical fiber to deliver the drug. Due to the complex interaction between light, photosensitizer and oxygen and the heterogeneity of light and drug distribution in the prostate, current approaches to treatment planning are computationally demanding. Non-patent document 9. Computational requirements prevent real-time intraoperative adjustment.

  The second problem is that there is a light dose threshold that is effective for treatment, and this threshold dose varies widely between patients receiving the same photosensitizer and planning fiber placement and light dose according to the same algorithm. It arises from the clinical observation that it is considered. Non-patent document 9. This presents challenges in selecting light doses prior to treatment and in planning effective treatments.

  Accordingly, there is a continuing need for methods that can determine a therapeutically effective threshold dose prior to treatment. There is a further need for treatment planning software that incorporates such treatment effective threshold dose calculations into the planning algorithm.

Koudinova et al., “Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): succesful in vivo treatment of human prosthetic small cell. J. et al. Cancer 104 (6): 782-9 (2003) Weersink et al., “Techniques for delivery and monitoring of TOOKAD (WST09) —mediated photothermal of the propotype: clinical exploration. 79 (3): 211-22 (2005) Trachtenberg et al., "Vascular targeted Photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response," J Urol. 178 (5): 1974-9 (2007) Trachtenberg et al., “Vascular-targeted photothermal therapy, padded fins, in the United States of Japan, Japan, Japan, and the United States. 102 (5): 556-62 (2008) Madar-Balakirski et al., “Permanent occlusion of feeding artists and draining veins in solid mouse tumors by th Mazor et al., "WST-11, A Novel Water-soluble Bacteriochlorophyll Derivative: Cellular Uptake, Pharmacokinetics, Biodistribution and Vascular-targeted Photodynamic Activity Using melanoma Tumors as a Model", Photochemistry & Photobiology 81: 342~351, pp. (2005) Brandis et al., "Novel Water-soluble Bacteriochlorophill Derivatives for Vascular-targeted Photodynamic Therapy: Synthesis, solubility, Phototoxicity and the Effect of Serum Proteins", Photochemistry & Photobiology 81: 983~993, pp. (2005) Ashur et al., “Photocatalytic Generation of Oxygen Radicals by the Water-Soluble Bacteriochlorophyll Deliverable WST-11, Noncovalently Bound Summin. Phys. Chem. A113: 8027-8037 (2009) Davidson et al., “Treatment planning and dose analysis for interstitial photodynamic thermal of cancer”, Phys. Med. Biol. 54: 2293-2313 (2009)

We use a photosensitizing agent, palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide (WST11; TOOKAD® Soluble ™) Have discovered that a light density index ("LDI") can be calculated that predicts the effectiveness of photodynamic treatment of prostate tumors. The prediction of efficacy is verified by MRI as early as 1 week after treatment and further confirmed by a negative biopsy 6 months after treatment. LDI can be used to determine a therapeutically effective light dose threshold from past data. It is easily computable, can be used in prospective treatment plans to increase the likelihood of successful treatment, potentially increasing the likelihood of treatment success while potentially reducing computational complexity without significantly increasing Provides dose parameters.

  Accordingly, in a first aspect, a method for treating prostate cancer is provided. The method involves administering a photosensitizer systemically to a patient having a prostate tumor and then delivering light of the appropriate wavelength through at least one optical fiber placed proximal to the tumor. Activating a sensitizer, wherein the light dose administered is above a light density index (LDI) threshold effective for a predetermined treatment.

  In various embodiments, a therapeutically effective LDI threshold is pre-determined from past data obtained using the same photosensitizer. In certain embodiments, historical data is obtained using the same photosensitizer administered at the same systemic dose, and sometimes the same wavelength as the same photosensitizer administered at the same systemic dose. From past data obtained using the delivered light.

  In various conventional embodiments, the photosensitizer is administered intravenously.

In certain embodiments, the photosensitizing agent is palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof, including dipotassium salt. . Palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof is 3-6 mg including a dose of 4 mg / kg in certain embodiments. / Kg administered intravenously. In a specific embodiment using this photosensitizer, the dose of light delivered is 200 J / cm and the LDI threshold is 1.0.

  In some embodiments, actinic rays are typically delivered through a plurality of optical fibers that are placed using a perineal brachytherapy template. Usually, light is delivered at a wavelength that approximates the absorption maximum of a photosensitizer administered systemically.

  In a related aspect, the photodynamics of prostate cancer are administered systemically and then activated by delivery of light of the appropriate wavelength through at least one optical fiber placed proximal to the tumor. An improved treatment method is shown. Improvements include delivering a light dose above a light density index (LDI) threshold effective for a predetermined treatment.

  In a further aspect, the therapeutically effective light density index threshold improves planning for photodynamic therapy specific to prostate cancer patients, including planning photodynamic therapy targeting blood vessels in prostate cancer. Used in the same way. The improved method includes setting the total length of the irradiated fiber to be used for treatment based on the planned treatment volume (PTV) and a pre-determined effective light density index threshold for the treatment.

  In a typical embodiment, the total length of the irradiated fiber is calculated as the product of the PTV and a predetermined treatment effective light density index threshold or a scalar multiple thereof. The effective LDI threshold for treatment is usually from historical data obtained from the use of the same photosensitizing drug, and more often from historical data using the same photosensitizing drug administered at the same systemic dose. Determined in advance. In certain embodiments, a therapeutically effective LDI threshold is determined from historical data obtained from the use of the same photosensitizer administered at the same systemic dose, the same wavelength of delivered light and the same light density. Is done.

  In a further aspect, a computer program product for treatment planning is presented. The program product is executed by a computer that implements computer-readable materialized program code and a method for creating a patient-specific, improved treatment plan for photodynamic treatment of prostate cancer. Including a computer usable medium having computer readable program code adapted thereto. A computer-implemented method includes setting a total length of illumination fiber required for effective treatment based on a planned treatment volume (PTV) and a pre-determined effective light density index threshold for the treatment. .

  In some embodiments, the total length of the irradiated fiber is calculated as the product of the PTV and a predetermined treatment effective light density index threshold or a scalar multiple thereof. A therapeutically effective LDI threshold is, in some embodiments, pre-determined from past data where the same photosensitizing agent intended for the intended use is used. In various embodiments, the therapeutically effective LDI threshold is the use of the same photosensitizer administered at the same systemic dose, as well as the same photosensitizer administered at the same systemic dose, delivered at the same wavelength. And determined in advance from past data obtained from the same light density.

  In a further aspect, a predetermined photosensitizer is administered to the patient and then at a predetermined wavelength through at least one illumination fiber designed to be inserted over the length of the insertion into the treatment area. A computer-aided auxiliary method is presented to plan the patient's treatment with photodynamic therapy that must be subjected to irradiation. Auxiliary methods are to calculate the planned treatment volume, PTV of the treatment area; to determine the effective light density index, LDI, threshold for treatment; and the planned treatment volume, PTV and said pre-determined Setting a total length of the at least one illumination fiber to be used for treatment based on a light density index threshold effective for the treated treatment.

We use a photosensitizing agent, palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide (WST11; TOOKAD® Soluble ™) Have discovered that a light density index ("LDI") can be calculated that predicts the effectiveness of photodynamic treatment of prostate tumors. The prediction of efficacy is verified by MRI as early as 1 week after treatment and further confirmed by a negative biopsy 6 months after treatment. LDI can be used to determine a therapeutically effective light dose threshold from past data. It can be used in prospective treatment plans to increase the likelihood of successful treatment, potentially increasing the likelihood of treatment success while potentially reducing computational complexity without significantly increasing it Provide complete dose parameters.

  Accordingly, in a first aspect, a method for treating prostate cancer is provided. The method involves administering a photosensitizer systemically to a patient having a prostate tumor and then delivering light of the appropriate wavelength through at least one optical fiber placed proximal to the tumor. Activating a sensitizer, wherein the light dose administered is above a light density index (LDI) threshold effective for a predetermined treatment.

LDI
The light density index (“LDI”) is calculated as follows: LDI = Σ (n) L / PTV
[Where Σ (n) L is the total length of all irradiated fibers and PTV is the planned treatment volume]. In a typical embodiment, the length of all irradiated fibers is measured in centimeters and the planned treatment volume is measured in milliliters.

  The patient specific PTV used in the calculation of LDI is planned using known treatment planning approaches. In some embodiments, the PTV is obtained by volume reconstruction from a series of MRI images of the patient's prostate, usually all of which have a tumor margin outline drawn, usually a transverse series. Led. In certain embodiments, tumor margin identification is performed by image recognition software and is typically subsequently reviewed by a radiologist or surgeon, but the tumor margin outline in a cross-sectional image is typically Performed by a radiologist or surgeon. Volume reconstruction is performed using standard digital image processing techniques and algorithms. In a typical embodiment, the PTV is planned to include an additional surrounding volume to ensure that the treatment is sufficient to completely include the actual tumor margin. In such an embodiment, the treatment planning software typically adds a margin selected by the user or predetermined by the software to each two-dimensional cross-sectional image that surrounds the tumor margin. In some embodiments, margins can be added after volume reconstruction, but this computationally more complex approach is not currently preferred. In some embodiments, PTV may be obtained from Davidson et al., “Treatment planning and dose analysis for interstitial photothermal of prostate cancer”, Phys. Med. Biol. 54: 2293-2313 (2009).

LDI threshold effective for treatment An LDI threshold effective for treatment is determined prior to treatment. In a typical embodiment, a therapeutically effective LDI threshold is pre-determined from past clinical data.

  In a typical embodiment, a therapeutically effective LDI threshold is first determined by correlating the magnitude of therapeutic LDI for each of a series of past patients with one or more later observed patient specific outcomes. The Subsequent outcomes are selected from technically recognized outcomes including clinical outcomes such as post-treatment survival, tumor stage or grade changes, and more generally evidence of tissue necrosis on post-treatment MRI Or selected from radiological and / or pathological results recognized in the art as useful surrogates, such as the percentage of post-treatment negative biopsies.

  In some embodiments, the treatment LDI is calculated from past data using the actually treated volume (ATV) instead of the past prospective PTV. ATV is effective from areas of necrosis observed in post-treatment MRI images such as MRI images taken 1 week after treatment, 1 month after treatment, 2 months after treatment, 3 months after treatment and / or 6 months after treatment Is calculated. In certain embodiments, an ATV is a series of post-treatment MRI images of a patient's prostate, usually transformed, of which the outline of the margin of a necrotic or hypoperfused region is usually drawn. Derived from the Bath series by volume reconstruction. In certain embodiments, marginal identification is performed by image recognition software and is typically subsequently reviewed by a radiologist or surgeon, but the outline of the necrotic or hypoperfused region in the cross-sectional image is Usually performed by a radiologist or surgeon. Volume reconstruction is performed using standard digital image processing techniques and algorithms.

  In a typical embodiment, a standard statistical approach is applied to the correlated treatment LDI and performance data to determine a therapeutically effective threshold that provides the desired degree of statistical confidence. For example, in Example I below, we have a P value of <0.01 for the prediction of necrosis volume on MRI at 1 week after treatment as a percentage of PTV, and at 6 months after treatment Confirming effective LDI thresholds for treatments with P values <0.01 with respect to the percentage of negative biopsies. An effective LDI threshold for any selected treatment may provide different magnitudes of statistical significance for different outcomes.

  Since a therapeutically effective LDI threshold can vary depending on the choice of photosensitizer, its systemic dosage and the irradiation wavelength delivered locally to the prostate, a therapeutically effective LDI threshold is used in the subject patient. Efficiently derived from historical data derived from previous clinical use of the same photosensitizing drug planned. In some embodiments, historical data is obtained from the use of the same photosensitizer administered at the same systemic dose that is to be used in the subject patient. In some embodiments, historical data is obtained from the use of the same photosensitizer administered at the same systemic dose irradiated at the same wavelength that is to be used in the subject patient. Furthermore, since a therapeutically effective LDI threshold can vary depending on the light density (eg, in joules / cm) delivered through each fiber, a therapeutically effective LDI threshold will be used in the target patient. Effectively derived from past data derived from previous clinical use of the same light density.

  A pre-determined effective LDI threshold for treatment does not require recalculation from past data for each patient being treated. In a typical embodiment, the treatment effective LDI threshold is treated by the treatment planning algorithm as a constant, usually entered by the user. However, a therapeutically effective LDI threshold may be recalculated periodically as more historical data becomes available, such as additional patient data and / or additional performance data for patients included in previous calculations. Conceivable. Further, in certain embodiments, a therapeutically effective LDI threshold is calculated separately for a defined subpopulation of past patients and the therapeutically effective LDI threshold used to administer treatment to a given patient. Are selected based on patient similarity to past subpopulations.

The effectiveness of the LDI parameters for predicting the photosensitizer therapeutic efficacy is determined by the photosensitizer, palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide (WST11). ; Demonstrated using TOOKAD (R) Soluble (TM) as the dipotassium salt;

Thus, in a preferred embodiment of the method of this aspect of the present invention, the photosensitizing agents are palladium 3 ¹ - oxo -l5- methoxycarbonylmethyl - Rodos bacteriochlorin 13 1 ^- (2-sulfoethyl) amide or their pharmaceutically acceptable Salt. The WST11 compound, in its non-ionized form, has the structure shown below in formula (Ia), where the tetrapyrrole carbons are numbered according to standard IUPAC nomenclature:

In various embodiments, the pharmaceutically acceptable WST11 salt is selected from monovalent and divalent alkali and alkaline earth metal cations such as one or more of K ⁺ , Na ⁺ , Li ⁺ and Ca ^2+. Effective counter ions. In a currently particularly preferred embodiment, a dipotassium salt as shown in formula Ib is used:

  Compounds of formula Ia and Ib are prepared according to known procedures. See WO 2004/045492 and US pre-grant application publication number US 2006/01422260 Al, the disclosure of which is incorporated herein by reference in its entirety.

  In other embodiments, the photosensitizer is a compound of formula II:

[Where:
M represents a metal atom selected from 2H or divalent Pd, Pt, Co, Sn, Ni, Cu, Zn and Mn and trivalent Fe, Mn and Cr;
R ₁ , R ₂ and R ₄ are each independently Y—R ₅ ;
Y is O, S or NR ₅ R ₆ ;
R ₃ is —CH═CH ₂ , —C (═O) —CH ₃ , —C (═O) —H, —CH═NR ₇ , —C (CH ₃ ) ═NR ₇ , —CH ₂ —OR. ₇ , —CH ₂ —SR ₇ , —CH ₂ —NR ₇ R ′ ₇ , —CH (CH ₃ ) —OR ₇ , —CH (CH ₃ ) —SR ₇ , —CH (CH ₃ ) —NR ₇ R ′ _{7, -CH (CH 3) Hal} , -CH 2 -Hal, -CH 2 -R 7, -CH = CR 7 R '7, -C (CH 3) = CR 7 R' 7, -CH = CR 7 _Hal, are selected from _{-C (CH 3) = CR 7} Hal and -C≡CR _7;
R ₅ , R ₆ , R ₇ and R ′ ₇ are each independently H or selected from the group consisting of:
(A) optionally containing one or more heteroatoms, carbocyclic or heterocyclic moieties, and / or optionally halogen, oxo, OH, SH, CHO, NH ₂ , CONH ₂ , C ₁ -C optionally substituted by one or more functional groups selected from the group consisting of negatively charged groups and acidic groups that are converted to negatively charged groups at physiological pH ₂₅ hydrocarbyl;
(B) an amino acid, peptide or protein residue; and (c) when Y is O or S, R ₅ may further be R ₈ ⁺ ;
m is 0 or 1;
R ₈ ⁺ is H ⁺ or a cation,
However,
(I) At least one, preferably two, of R ₅ , R ₆ , R ₇ and R ′ ₇ are acidic groups that are converted by negatively charged groups or to negatively charged groups at physiological pH A hydrocarbon chain as defined in (a) above, or (ii) at least one, preferably two, of R ₁ , R ₂ and R ₄ are OH, SH, O ^- _R ^{8 +} a either - R ₈ ⁺ or ^S; at least one of or _{(iii) R} 1, R ₂ and _{R ^{4, OH, SH, O - R}} 8 + or ^S - _R ^{8 +} a is , R ₅ , R ₆ , R ₇ and R ′ ₇ are hydrocarbon chains substituted by a negatively charged group or by an acidic group converted to a negatively charged group at physiological pH or it; or _(iv) R 1, _{R 2} and _{R 4} At least one _{^{blood, OH, SH, O - R}} 8 + or ^S - is _R ^{8 _+,} at least one of R _5, R 6, _{R 7} and R _'7 is an amino acid, peptide, or protein Or (v) at least one of R ₅ , R ₆ , R ₇ and R ′ ₇ is converted to a negatively charged group or to a negatively charged group at physiological pH. A hydrocarbon chain substituted by an acidic group, wherein at least one of R ₅ , R ₆ , R ₇ and R ′ ₇ is an amino acid, peptide, or protein residue,
A compound of formula I, wherein M is as defined, R ₃ is —C (═O) CH ₃ , R ₁ is OH or OR ₈ ⁺ , and R ₂ is —OCH ₃ , and Compounds of formula II wherein M is 2H, R ₃ is —C (═O) CH ₃ , R ₁ , R ₂ and R ₄ are OH and m is 0 or 1 are excluded.

In various embodiments of the photosensitizer of formula II, the negatively charged group is selected from the group consisting of COO ⁻ , COS ⁻ , SO ₃ ⁻ and / or PO ₃ ²⁻ . In various embodiments, the acidic group that is converted to a negatively charged group at physiological pH is selected from the group consisting of COOH, COSH, SO ₃ H, and / or PO ₃ H ₂ . In certain embodiments, R ₁ is Y—R ₅ ; Y is O, S, or NH; R ₅ is OH, SH, SO ₃ H, NH ₂ , CONH ₂ , COOH, COSH, A hydrocarbon chain substituted by a functional group selected from PO ₃ H ₂ . In selected embodiments, R ₅ is an amino acid, peptide or protein residue. It is useful that M is a divalent palladium atom.

In certain embodiments of the photosensitizer of formula II:
M represents 2H, divalent Pd, Cu or Zn or trivalent Mn;
R _{1 ^{is, -O - R 8 +, -NH-}} (CH 2) n -SO 3 - R 8 +, -NH- (CH 2) n -COO - R 8 +; -NH- (CH 2) n —PO ₃ ²⁻ (R ₈ ⁺ ) ₂ ; or Y—R ₅ , wherein Y is O, S or NH, and R ₅ is an amino acid, peptide or protein residue;
R ₂ is C ₁ -C ₆ alkoxy, such as methoxy, ethoxy, propoxy, butoxy, more preferably methoxy;
R _{3 is, -C (= O) -CH 3} , -CH = N- (CH 2) n -SO 3 - R 8 +; -CH = N- (CH 2) n -COO - 8 +; -CH ^{_{= N- (CH 2) n -PO}} 3 2 - (R 8 +) 2; -CH 2 -NH- (CH 2) n -SO 3 - R 8 +; -NH- (CH 2) n -COO - R ₈ ⁺ ; or —NH— (CH ₂ ) _n —PO ₃ ²⁻ (R ₈ ⁺ ) ₂ ;
R _{4 ^{is, -NH- (CH 2) n -SO}} 3 - R 8 +; -NH- (CH 2) n -COO - R 8 +; -NH- (CH 2) n -PO 3 2 (R 8 ⁺ ) ₂ ; R ₈ ⁺ is a monovalent cation such as K ⁺ , Na ⁺ , Li ⁺ , NH ₄ ⁺ , more preferably K ⁺ ;
m is 1, and n is an integer of 1 to 10, preferably 2 or 3.

In certain embodiments of the photosensitizer of formula II:
M is divalent Pd;
R _{1 ^{is, -O - R 8 +, -NH-}} (CH 2) n -SO 3 - R 8 + , or a _{Y-R 5,} wherein, Y is, O, S or NH, _{R 5} Is an amino acid, peptide or protein residue;
R ₂ is C ₁ -C ₆ alkoxy, preferably methoxy;
R _{3 is, -C (= O) -CH 3} , -CH = N- (CH 2) n -SO 3 - R 8 + , or _{-CH 2 -NH- (CH 2) n} -SO 3 - R 8 + Is;
R _{4 ^{is, -NH- (CH 2) n -SO}} 3 - R 8 +; NH- (CH 2) n -COO - R 8 +; NH- (CH 2) n -PO 3 2 - (R 8 + ₂ ); R ₈ ⁺ is a monovalent cation, preferably K ⁺ ;
m is 1, and n is 2 or 3.

  Compounds of formula II can be synthesized according to the procedures described in WO 2004/045492 and US pre-grant application publication number US 2006/01422260 Al, the disclosure of which is incorporated herein by reference in its entirety.

  In a typical embodiment, the photosensitizer is administered intravenously. In certain embodiments, the photosensitizer is administered by intravenous infusion. In other embodiments, the photosensitizing agent is administered as an intravenous bolus.

In certain embodiments where the photosensitizer is WST11 or a pharmaceutically acceptable salt thereof, the photosensitizer is administered intravenously at a dose of about 2-6 mg / kg. In certain embodiments, WST11 or a salt thereof is administered intravenously at a dose of about 2 mg / kg, 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or even about 6 mg / kg. In one series of embodiments, the photosensitizer is palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rodobacteriochlorin 13 ^1- (2-sulfoethyl) amide dipotassium salt administered intravenously at 4 mg / kg. is there.

The wavelength of light delivered is appropriate for the selected photosensitizer and, in normal embodiments, approximates the absorption maximum of the drug.

  In embodiments where the photosensitizer is WST11 or a salt thereof, the wavelength will typically be between about 670 and about 780 nm. In various embodiments, the wavelength will be about 750 nm, including about 753 nm.

  In another aspect, an improved method for planning photodynamic therapy is provided. Improvements include setting the overall length of the irradiated fiber used for treatment based on the planned treatment volume (PTV) and a pre-determined effective light density index threshold for the treatment. As will be appreciated, the length of the illumination fiber refers to the length of the optical fiber that is placed in the prostate tissue and can deliver light to that tissue.

  In a typical embodiment, the total length of all irradiated fibers is calculated as a pre-determined therapeutic effective LDI threshold × PTV product or a scalar transform thereof. In a typical embodiment, the LDI threshold and PTV are determined as described above. In certain embodiments, the total length of all illumination fibers is provided by a single fiber. More generally, the total length of all irradiated fibers is contributed by multiple fibers. In some embodiments, all fibers are of the same length. In other embodiments, the fibers are different in length.

  The improvements may be used in conjunction with existing methods of treatment planning that are designed to optimize the placement of optical fibers for photodynamic treatment of prostate cancer. In some embodiments, for example, the total length of all irradiated fibers calculated as described above can be obtained from Davidson et al., “Treatment planning and dose analysis for interstitial phototherapy of promoters,” Med. Biol. 54: 2293-2313 (2009), used in conjunction with light-diffusion based treatment planning. In other embodiments, the total length of all irradiated fibers calculated as described above is used with other treatment planning algorithms.

  By establishing the overall length of the irradiating fiber, the improvement effectively reduces the number of variables to be considered while ensuring that the optimized fiber placement delivers a light dose above the therapeutic threshold. Reduce computational complexity. Thus, improvements can be incorporated to aid in software used to plan photodynamic therapy.

  Accordingly, in another aspect, a computer program product is provided that includes a computer usable medium having computer readable embodied program code. The computer readable program code was adapted to be executed by a computer performing a method for creating a patient specific treatment plan for photodynamic treatment of prostate cancer. The method includes setting the total length of the irradiated fiber to be used for treatment based on a planned treatment volume (PTV) and a predetermined light density index threshold effective for the treatment. In a typical embodiment, the PTV and the pre-determined effective treatment light density index threshold are calculated as described above, and the total length of the irradiated fiber is the pre-determined effective treatment LDI threshold × PTV. Calculated as a product or its scalar transform.

  Additional advantages and features are illustrated in the following examples, which are presented for purposes of illustration and should not be construed to limit the scope of the invention.

Example 1: Light density index predicts early efficacy of photodynamic therapy targeting localized blood vessels in prostate cancer.
Materials and Methods Palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amidodipotassium salt is disclosed in WO 2004/045492 and US 2006, the disclosure of which is hereby incorporated by reference in its entirety. / 0142260 as prepared.

  Men with low-risk organ-localized prostate cancer (Grayson 3 + 3 with a minimum of 10-core TRUS biopsy) were recruited for two continuing studies: PCM201 (dose escalation study) or PCM203 (confirmation study). A vascular-targeted photodynamic therapy (“VTP”) procedure performed under general anesthesia involves intravenous administration of TOOKAD® Soluble at 4 mg / kg, which is then treated with 200 J / Activated by low-power laser light delivered locally to the prostate through a perineal template in a brachytherapy format with a light density of cm. The planned treatment volume (“PTV”, mls) is determined by the location of the tumor by biopsy and MRI and varies from less than one lobe to the volume of the entire prostate.

  The light density index (“LDI”) is calculated as LDI = Σ (n) L / PTV, where Σ (n) L is the total length (cm) of all irradiated fibers, and PTV is planned Treatment volume (mls).

  The early therapeutic effect was determined as the percentage of PTV that showed a lack of gadolinium uptake on one week of MRI. This also correlated with the results of a 6-month transrectal ultrasound (TRUS) guided biopsy (positive or negative for any cancer).

  The correlation between the LDI on day 7 and the volume of tissue necrosis and the proportion of negative biopsies at 6 months were evaluated in the search for thresholds.

Results In two studies, 90 men were treated with a 4 mg / kg TOOKAD® Soluble dose and a light dose of 200 J / cm. Of these, 89 were analyzable for LDI. Results using an LDI threshold of 1 are shown below.

CONCLUSION LDI is a reliable predictor of therapeutic efficacy using TOOKAD® Soluble VTP, both for effects seen with 1 week MRI and 6 months biopsy.

  While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention.

Claims (44)

A method of treating prostate cancer comprising:
Administering the photosensitizer to the whole body of a patient having a prostate tumor;
Activating the photosensitizer by delivering light of an appropriate wavelength through at least one optical fiber disposed proximal to the tumor;
A method wherein the light dose administered is greater than or equal to a pre-determined therapeutically effective light density index (LDI) threshold.   The method of claim 1, wherein a therapeutically effective LDI threshold is pre-determined from past data obtained from use of the same photosensitizer.   3. The method of claim 2, wherein the therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose.   The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose and the same wavelength of delivered light. the method of. The photosensitizing agent is palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof. The method described. 6. The method of claim 5, wherein the photosensitizer is palladium 3 < ¹ > -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 < ¹ >-(2-sulfoethyl) amide dipotassium salt.   The method according to any one of claims 1 to 6, wherein the photosensitizer is administered intravenously. Palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof, wherein the photosensitizer is administered intravenously at 3 to 6 mg / kg. The method of claim 7, wherein   9. The method of claim 8, wherein the photosensitizer is administered at a dose of 4 mg / kg.   The method of claim 9, wherein the dose of light is 200 J / cm and the LDI threshold is 1.0.   11. A method according to any of claims 1 to 10, wherein light is delivered through a plurality of optical fibers.   The method of claim 11, wherein the optical fiber is deployed using a brachytherapy template.   13. The method of any of claims 1-12, wherein light is delivered at a wavelength that approximates the absorption maximum of a photosensitizer administered systemically. An improved photodynamic treatment method for prostate cancer comprising:
A photosensitizer is administered systemically and then activated by delivery of light of the appropriate wavelength through at least one optical fiber placed proximal to the tumor;
Delivering a light dose above a light density index (LDI) threshold effective for a predetermined treatment.   14. The method of claim 13, wherein a therapeutically effective LDI threshold is pre-determined from past data obtained from use of the same photosensitizer.   16. The method of claim 15, wherein the therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose.   17. The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose and the same wavelength of delivered light. the method of. The photosensitizing agent is palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof. The method described. Photosensitizing agent, palladium ^{3 1} - oxo -l5- methoxycarbonylmethyl - Rodos bacteriochlorin 13 ¹ - (2-sulfoethyl) amide dipotassium salt The method of claim 18.   20. A method according to any of claims 14 to 19, wherein the photosensitizer is administered intravenously. Palladium 3 ¹ -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 ^1- (2-sulfoethyl) amide or a pharmaceutically acceptable salt thereof, wherein the photosensitizer is administered intravenously at 3 to 6 mg / kg. 21. The method of claim 20, wherein   24. The method of claim 21, wherein the photosensitizer is administered at a dose of 4 mg / kg.   23. The method of claim 22, wherein the light dose is 200 J / cm and the LDI threshold is 1.0.   24. A method according to any of claims 14 to 23, wherein the light is delivered through a plurality of optical fibers.   25. The method of claim 24, wherein the optical fiber is deployed using a brachytherapy template.   26. The method of any of claims 1-25, wherein light is delivered at a wavelength that approximates the absorption maximum of a photosensitizer administered systemically. An improved method for planning photodynamic treatment of prostate cancer in a patient comprising
A method comprising setting a total length of illumination fibers used for treatment based on a planned treatment volume (PTV) and a pre-determined effective light density index threshold for the treatment.   28. The method of claim 27, wherein the total length of the irradiated fiber is calculated as a product of PTV and a predetermined treatment effective light density index threshold or a scalar multiple thereof.   29. The method of claim 28, wherein the therapeutically effective LDI threshold is pre-determined from past data obtained from use of the same photosensitizer.   30. The method of claim 29, wherein the therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose.   31. The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose and the same wavelength of delivered light. the method of.   The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizing agent, the same irradiation light wavelength and the same light density administered at the same systemic dose. The method described. A program product comprising a computer usable medium having computer readable program code embodied therein,
A computer readable program code is adapted to be executed by a computer for performing a method for generating a patient specific treatment plan for photodynamic treatment of prostate cancer, the method comprising: (PTV) and a program product that includes setting the total length of the irradiated fiber required for effective treatment based on a predetermined treatment effective light density index threshold.   34. The computer program product of claim 33, wherein the total length of the irradiated fiber is calculated as a product of PTV and a predetermined treatment effective light density index threshold or a scalar multiple thereof.   35. The computer program product of claim 34, wherein a therapeutically effective LDI threshold is pre-determined from past data obtained from use of the same photosensitizer.   36. The computer program product of claim 35, wherein the therapeutically effective LDI threshold is pre-determined from historical data obtained from the use of the same photosensitizer administered at the same systemic dose.   37. The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose and the same wavelength of delivered light. Computer program products.   The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer, the same light wavelength and the same light density administered at the same systemic dose. The computer program product described. An auxiliary method performed by a computer to plan treatment of a patient with photodynamic therapy,
A predetermined photosensitizer is administered to the patient and then subjected to irradiation at a predetermined wavelength through at least one irradiation fiber designed to be inserted over the length of the insertion into the treatment area. Must be
The following steps:
Calculating a planned treatment volume, PTV, of the treatment area;
Determining a therapeutically effective light density index, LDI, threshold;
Setting the total length of the at least one illumination fiber to be used for treatment based on a planned treatment volume, PTV and a light density index threshold effective for the predetermined treatment;
An auxiliary method characterized by comprising:   40. The auxiliary method according to claim 39, wherein the total length of the irradiated fiber is calculated as the product of the PTV and a predetermined treatment effective light density index threshold or a scalar multiple thereof.   41. The method of claim 40, wherein a therapeutically effective LDI threshold is pre-determined from past data obtained from use of the same photosensitizer.   42. The auxiliary method of claim 41, wherein the therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer administered at the same systemic dose.   43. The therapeutically effective LDI threshold is pre-determined from historical data obtained from the use of the same photosensitizer administered at the same systemic dose and the same wavelength of delivered light. Assisting method.   44. The therapeutically effective LDI threshold is pre-determined from past data obtained from the use of the same photosensitizer, the same light wavelength and the same light density administered at the same systemic dose. The auxiliary method described.